This application is a 371 of pct/FR00/00750, filed Mar. 24, 2000.
The present invention relates to a process for preparing xcex1,xcex2,xcex2-trisubstituted hydroxylamines, referred to hereinbelow as alkoxyamines, obtained from nitroxides, which can be used in particular as radical-polymerization initiators. The use of alkoxyamines such as those derived from (2,2,6,6-tetramethylpiperidyl)-N-oxide (TEMPO) in the preparation of macromolecules has given rise to many publications.
Thus, Hawker C. J. et al. (Macromolecules 1996, 29, pages 5245-5254) showed that the use of TEMPO-based alkoxyamines such as (2xe2x80x2,2xe2x80x2,6xe2x80x2,6xe2x80x2-tetra-methyl-1xe2x80x2-piperidyloxy)methylbenzene as initiators for the radical-mediated polymerization of styrene made it possible to control the polymerization and to gain access to well-defined polymers with low polydispersity indices, and they found that the polymerization rates were substantially equivalent to the rates obtained when they used conventional initiators such as AIBN or benzoyl peroxide in the presence of TEMPO.
Alkoxyamines can be prepared according to methods known in the literature. The most common method involves the coupling of a carbon radical with a nitroxide radical.
If an alkoxyamine is denoted by: 
Y1, Y2, Y3, Y4, Y5, Y6, Z being defined later, the carbon radical Z* can be generated by various methods described in the literature: decomposition of an azo compound, abstraction of a hydrogen atom from a suitable substrate, addition of a radical to an olefin. The radical Z* can also be generated from an organometallic compound such as an organomagnesium reagent Z-MgX as described by Hawker C. J. et al. in Macromolecules 1996, 29, 5245-5254 or from a halo derivative Z-X in the presence of an organometallic system such as CuX/bipyridine (X=Cl or Br) according to a reaction of ATRA (Atom Transfer Radical Addition) type as described by Dorota Greszta et al. in Macromolecules 1996, 29, 7661-7670.
One of the methods most commonly used for preparing alkoxyamines (I) is the method involving the ATRA reaction.
This method consists in transferring an atom or a group of atoms onto another molecule in the presence of a CuX/bipyridine organometallic system, in solvent medium, according to the scheme: 
In the organometallic system, X preferably represents a bromine atom.
The procedure generally used consists in dissolving the organometallic system such as CuBr/bipyridine in an organic solvent, preferably an aromatic solvent such as benzene or toluene, and then in introducing the compound ZX and the nitroxide (II) into the solution.
This approach has the major drawback of requiring long reaction times, that are unacceptable for an industrial preparation of alkoxyamines, or of using a large excess of one of the reagents.
Furthermore, the organometallic system used involves expensive ligands (bipyridine or derivatives).
In addition, the removal of the residual metal from the products obtained is difficult, requiring expensive purification operations such as passing the products through a column of silica.
Thus, in international patent application WO 9B/40415, for example, Matyjaszewski K. et al. obtain 1-(2,2,6,6-tetramethylpiperidyloxy)-1-phenylethane in a yield of 69% after purification by column chromatography, by reactingTEMPO and (1-bromoethyl)benzene in a TEMPO/(1-bromoethyl)benzene molar ratio of 2 (i.e. a molar excess of TEMPO equal to 100%) for 2 hours at 90xc2x0 C., in the presence of an organometallic system [4,4xe2x80x2-bis(5-nonyl)-2,2xe2x80x2-bipyridine/Cu(OTf)2/Cu0].
A process has now been found for preparing alkoxyamines of formula: 
from nitroxides: 
the said process consisting in reacting the said nitroxide (II) with a halocarbon compound ZX in which X represents a chlorine, bromine or iodine atom, in a water-immiscible organic solvent medium, in the presence of an organometallic system MA (L)n (III) in which:
M represents a metal such as Cu, Ag or Au,
A represents a halogen atom, a carboxylate group or a triflate group,
L represents a ligand for the metal M,
n is 1, 2 or 3, according to the scheme: 
xe2x80x83the said process being characterized in that it consists in carrying out the following steps:
a) a metal salt MA, the ligand L, the halocarbon compound ZX and the nitroxide (II) are mixed together with stirring, in an organic solvent, in a ZX/nitroxide (II) molar ratio ranging from 1 to 1.4,
b) the reaction medium is kept stirring at a temperature of between 20xc2x0 C. and 90xc2x0 C. until the nitroxide (II) has completely disappeared,
c) the organic phase is recovered and washed with water, and then
d) the alkoxyamine (I) is isolated by evaporating the organic solvent under reduced pressure.
Preferably, M represents Cu, A represents a halogen such as Cl or Br, a carboxylate group such as acetate or a triflate group, and X represents a chlorine atom or a bromine atom.
According to the present invention, the ligand L for the metal M in the organometallic system (III) is chosen from the compounds represented by the general formula (IV): 
in which R1, R2, R3 and R4, which may be identical or different, represent a hydrogen atom, a linear or branched alkyl group containing a number of carbon atoms ranging from 1 to 10 and preferably ranging from 1 to 4, R5 represents a hydrogen atom, a linear or branched alkyl group containing a number of carbon atoms ranging from 1 to 10 and preferably ranging from 1 to 4, a residue 
in which R6 and R7 have the same meanings as R5, or alternatively at least two of the radicals R1, R2, R3, R4 and R5 may be linked together to form a ring; m, p and q, which may be identical or different, represent integers ranging from 1 to 4, preferably equal to 2, x ranging from 0 to 4.
By way of illustration of ligands L represented by formula (IV) mention will be made of:
tris [2-(dimethylamino)ethyl]amine: 
xe2x80x83N,N,Nxe2x80x2,Nxe2x80x2,Nxe2x80x3-pentamethyldiethylenetriamine (PMDETA): 
xe2x80x83N,N,Nxe2x80x2,Nxe2x80x2-tetramethylethylenediamine:
(CH3)2xe2x80x94Nxe2x80x94CH2CH2xe2x80x94Nxe2x80x94CH3)2,
xe2x80x831,1,4,7,10,10-hexamethyltriethylenetetramine (HMTETA): 
xe2x80x83cyclic polyamines such as:
1,4,7-trimethyl-1,4,7-triazacyclononane,
1,5,9-trimethyl-1,5,9-triazacyclododecane,
1,4,8,11-tetramethyl-1,4,8,11-tetraazacyclotetradecane.
PMDETA will preferably be used.
The process according to the invention consists in mixing, with stirring, a metal salt MA, the ligand L, the compound ZX and the nitroxide (II) in an organic solvent which is preferably an aromatic hydrocarbon such as benzene, toluene or xylenes, or an alkylchloride such as CH2Cl2 or alternatively an ether.
The oxidation state of the active species of the metal M is equal to 1 (MI)
According to the present invention, this active species can be added, without modification, to the reaction medium, preferably in the form of a metal halide MIA.
The preferred metal halide is CuBr.
The active species can also be generated in situ according to the redox reaction:
MIIA+MO⇄2MIA
from a metal salt MIIA in which the metal M is in oxidation state 2 (MII) and the same metal in oxidation state zero (MO).
According to this variant, the metal halide MIIA which is preferred is CuBr2.
According to another variant, a metal salt MA in which the metal M is in oxidation state 1 (MIA) and the same metal M in oxidation-state zero (MO) may also be introduced into the reaction medium.
The ligand L is used in an L/MI molar ratio ranging from 1 to 5 and preferably ranging from 1 to 2.
The ZX/nitroxide (II) molar ratio ranges from 1 to 1.4 and is preferably equal to 1.
The reaction mixture is then stirred at a temperature of between 20xc2x0 C. and 90xc2x0 C. and preferably in the region of room temperature.
The process is performed under an atmosphere of inert gas such as nitrogen or argon and preferably at atmospheric pressure.
The reaction times are very short. The end of the reaction can be monitored by the disappearance of the reagents, by chromatographic methods (GC, HPLC, TLC). Once the reaction is complete,. any precipitate obtained. is filtered off, rinsed, preferably with the same solvent used in the reaction, and the organic phase is then washed with water until the extracted aqueous phases become colorless.
The organic solvent is removed under reduced pressure, preferably at room temperature, and the alkoxyamine is recovered.
According to the invention, the water used to wash the organic phase can contain one or more salts in weight amounts that are not more than the solubility limit of the said salts in water at room temperature.
These salts will preferably be chosen from alkali metal salts, ammonium salts and alkylammonium salts of chloride, formate or oxalate.
By way of illustration of such salts which can be used according to the present invention, mention will be made of sodium chloride, ammonium. formate, triethylammonium formate and diammonium oxalate.
The alkoxyamines may be characterized by elemental analysis, HPLC, IR and NMR.
The process according to the invention has the advantage of being carried out with commercially available ligands. The reaction between the nitroxide (II) and the halocarbon compound ZX is fast. The removal of the metal M of the organometallic system MAa(L)n is particularly easy to carry out by simple washing with water.
The process according to the invention produces alkoxyamines that are virtually free of metal M.
In the alkoxyamines obtained according to the process of the invention, the content of metal M is less than 10 ppm.
In addition, the alkoxyamine yields are high.
The process according to the invention applies most particularly to the preparation of alkoxyamines of formula: 
from nitroxides of formula: 
in which formulae the groups Y1 to Y6, which may be identical or different, represent a hydrogen atom, a linear or branched alkyl radical containing a number of carbon atoms ranging from 1 to 10, a cycloalkyl radical containing a number of carbon atoms ranging from 3 to 20, a halogen atom, a cyano radical, a phenyl radical, a hydroxyalkyl radical containing a number of carbon atoms ranging from 1 to 4, a dialkoxyphosphonyl or diphenoxyphosphonyl radical, an alkoxycarbonyl or alkoxycarbonylalkyl radical, or alternatively two or more of the groups Y1 to Y6 can be linked with the carbon atom which bears them to form cyclic structures, which can comprise one or more exocyclic functions chosen from: HOxe2x80x94, CH3C(O)xe2x80x94, CH3Oxe2x80x94, H2Nxe2x80x94CH3C(O)NHxe2x80x94, (CH3)2Nxe2x80x94; or alternatively can comprise one or more exocyclic or endocyclic hetero atoms such as O or N;
Z is a residue of formula 
in which W1, W2 and W3, which may be identical or different, represent a hydrogen atom, a linear or branched alkyl radical containing a number of carbon atoms ranging from 1 to 10, a phenyl radical, a benzyl radical, a cyano radical, a cycloalkyl radical containing a number of carbon atoms ranging from 3 to 12; a radical xe2x80x94(CH2)rC(O)OW4 in which W4 represents a linear or branched alkyl containing a number of carbon atoms ranging from 1 to 6, r=0 to 6;
X represents a chlorine, bromine or iodine atom.
By way of illustration of nitroxides (II) which can be used according to the present invention, mention will be made of:
2,2,5,5-tetramethyl-1-pyrrolidinyloxy (generally sold under the trade name PROXYL);
3-carboxy-2,2,5,5-tetramethylpyrrolidinyloxy (commonly known as 3-carboxy PROXYL);
2,2,6,6-tetramethyl-1-piperidyloxy (commonly known as TEMPO);
4-hydroxy-2,2,6,6-tetramethyl-1-piperidyloxy (commonly known as 4-hydroxy-TEMPO);
4-methoxy-2,2,6,6-tetramethyl-1-piperidyloxy (commonly known as 4-methoxy-TEMPO);
4-oxo-2,2,6,6-tetramethyl-1-piperidyloxy (commonly known as 4-oxo-TEMPO);
4-amino-2,2,6,6-tetramethyl-1-piperidyloxy (commonly known as 4-amino-TEMPO);
4-acetamido-2,2,6,6-tetramethyl-1-piperidyloxy (commonly known as 4-acetamido-TEMPO);
N-tert-butyl-1-phenyl-2-methylpropyl nitroxide,
N-(2-hydroxymethylpropyl)-1-phenyl-2-methylpropyl nitroxide,
N-tert-butyl-1-diethylphosphono-2,2-dimethylpropyl nitroxide,
N-tert-butyl-1-dibenzylphosphono-2,2-dimethylpropyl nitroxide,
N-tert-butyl-1-di(2,2,2-trifluoroethyl)-phosphono-2,2-dimethylpropyl nitroxide,
N-tert-butyl-[(1-diethylphosphono)-2-methylpropyl]nitroxide,
N-(1-methylethyl)-1-cyclohexyl-1-(diethylphosphono) nitroxide,
N-(1-phenylbenzyl)-[(1-diethylphosphono)-1-methylethyl]nitroxide,
N-phenyl-1-diethylphosphono-2,2-dimethylpropyl nitroxide,
N-phenyl-1-diethylphosphono-1-methylethyl nitroxide,
N-(1-phenyl-2-methylpropyl)-1-diethylphosphonomethylethyl nitroxide,
bis-1-oxyl-2,2,6,6-tetramethylpiperid-4-yl sebacate
sold under the brand name xe2x80x9cCXA 5415xe2x80x9d by the company CIBA SPEC. CHEM.
By way of illustration of compounds ZX which can be used, mention will be made of the compounds of formula: C6H5CH2Br, (CH3)2C(CN) Br, CH3OC(O)C(CH3)2Br, CH3OC(O)CH(CH3)Br, C6F13I.
The alkoxyamines of formula (I) obtained according to the process of the present invention can be used for the polymerization and copolymerization of any monomer containing a carbon-carbon double bond which can undergo radical-mediated polymerization. The polymerization or copolymerization is carried out under the usual conditions known to those skilled in the art, taking into account the monomer(s) under consideration. The monomers under consideration may be a vinylaromatic monomer (styrene, substituted styrenes), a diene or an acrylic or methyacrylic monomer. The monomer may also be vinyl chloride, vinylidene difluoride or acrylonitrile.